INTERVIEW WITH A RESEARCHER
Testing a
Simple Strategy
To Prevent
Schizophrenia
via Dietary
Supplements
by Peter Tarr, Ph.D.
ROBERT FREEDMAN, M.D.
Chair of Psychiatry
University of Colorado
Editor-in-Chief
The American Journal of Psychiatry
Foundation Scientific Council Member
2015 Lieber Prize for
Outstanding Schizophrenia Research
2006, 1999 Distinguished Investigator
8 Quarterly May 2016
AT WHAT POINT do the fruits of basic research—the
hard-won bits and pieces of knowledge about brain function
that the Foundation’s grants generate—result in the development of new treatments? There’s an exciting example now
emerging in the laboratory run by Robert Freedman, M.D.
Dr. Freedman, Chair of Psychiatry at the University of Colorado, editor in chief of The American Journal of Psychiatry,
and a member of the Foundation’s Scientific Council since
2001, has been on a long journey that began in medical
school at Harvard in the late 1960s.
The winner of the 2015 Lieber Prize for Outstanding Schizophrenia Research and twice (2006, 1999) a Distinguished
Investigator, Dr. Freedman has been on the trail of what
neuroscientists call inhibition—specifically, its role in
schizophrenia. Inhibition refers to the brain’s ability to dial
down the strength of signals being exchanged among excitatory nerve cells. In schizophrenia, evidence suggests that an
insufficiency in inhibition leads to hyperactivity in key areas
involved in cognition and emotional processing.
Much of what Dr. Freedman and his colleagues have learned
over decades has been translated into a simple and safe preventive strategy to bolster inhibition in the fetal brain, and
thereby lessen the risk and perhaps actually prevent some
newborn children from developing schizophrenia—one of
the great objectives in all medical research.
The strategy involves providing expecting mothers with
supplements of choline, an essential nutrient that plays an
outsized role in the fetal brain while it is developing in the
womb. The fetal brain is hyperactive as it assembles itself. “It
just fires up all of its nerve cells, no inhibition whatsoever,”
Dr. Freedman says. “Of the 20,000 genes we humans have,
more are devoted to building the brain than anything else.
And most of them are most active—about tenfold more—
before birth compared with after.”
Just before birth all this activity needs to quiet down, however. “The brain is settling down,” Dr. Freedman explains.
“This turns out to be the final step right before delivery, the
last of five or six distinct steps which correspond with major
changes in brain organization.” In each step, he says, “you
not only get more memory and more function—as you do
each time you upgrade your computer—but you also install
a new operating system. In the early brain, each operating
system is installed by the one that came before it.”
Robert Freedman, M.D.
Of the 20,000 genes we humans have,
more are devoted to building the brain than
anything else. And most of them are most
active—about tenfold more—before birth
compared with after.
Dr. Freedman’s research focuses on one of the earliest
operating systems, which unlike the others that follow it,
“hangs around to do the very last installation.” This final
step in the pre-birth developmental program makes normal
inhibition possible.
Evidence shows that in infants who go on to develop schizophrenia, the brain’s inhibitory system does not establish itself
as robustly as it should. The results are evident to those who
treat and spend time with patients, including Dr. Freedman,
still an active clinician.
“You may hear a patient say, ‘I vaguely overheard someone
talking and I concluded they were talking about me, and
that they were saying bad things.’ There is often a hypersensitivity to sound. When you investigate, the sound is
really there, but misinterpreted. You or I would probably
ignore it as noise, if we did hear it. We might say, ‘This is a
noisy apartment.’ But we wouldn’t say, ‘And they’re talking
about me.’”
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A hypersensitivity to sensory information, accompanied by
difficulty discriminating the nature or emotional salience
of the information, is characteristic in schizophrenia. It
can be traced biologically, at least in part, to a deficiency in
inhibition. There is too much excitation, not enough inhibition—as, indeed, Dr. Freedman and colleagues showed
in a schizophrenia study of the brain’s hippocampus, a vital
center for emotional processing. Even in its “resting state,”
this part of the brain is hyperactive in people with schizophrenia, the study showed.
Several converging lines of evidence have pointed Dr. Freedman to a gene called CHRNA7 (pronounced “CHUR-na
7”). Very active early in development, the gene quiets down
just before birth to a low activity level that continues into
adulthood. This is the gene, it turns out, that encodes receptors on nerve cells that become vital at the end of gestation,
in the emergence of neural inhibition. The receptors are
called alpha-7 nicotinic receptors, or α7 receptors.
CHRNA7 is the gene whose expression is most significantly
decreased in the brains of people who have had schizophrenia (as measured in postmortem brain analysis). Genetic
studies have also shown that a subset of schizophrenia
patients have genomes in which the area on chromosome 15
containing CHRNA7 is deleted, meaning they do not make
enough α7 receptors.
In adults, α7 receptors are activated by a neurotransmitter called acetylcholine. In related research, Dr. Freedman
and colleagues have been testing drugs that stimulate the
α7 receptor in adults with schizophrenia—who, presumably,
have had insufficient inhibitory activity from the time near
birth when the system is first activated.
In the fetus, it is choline in the mother’s amniotic fluid that
activates these receptors. Choline is needed throughout
pregnancy in considerable amounts for various purposes,
not only to prepare the brain’s inhibitory system but also to
build the walls of cells throughout the body. Studies show
that one expectant mother in five does not get enough choline in her diet. While meat and eggs are rich sources of
the nutrient, which is also found in many other foods, poor
diets do not supply nearly enough.
These facts led Dr. Freedman and colleagues to an experiment that has taken the last nine years to complete. They
wanted to know whether giving expectant mothers extra
choline in the second and third trimesters might help their
children develop more robust inhibitory capacity. [The
accompanying story explains how they conducted the experiment and showed that it works.]
“The larger story is that we’ve gone from learning ways in
which the nervous system doesn’t work in schizophrenia to
actually doing something to prevent it from happening,” says
Dr. Freedman. “This is the first group of children that we can
point to and say, yes, we can treat earlier and do it effectively.”
INTERVIEW WITH A RESEARCHER / SIDEBAR
Choline Supplementation in Mothers Has
Yielded Positive Results in Children
“We know that babies born to moms who have schizophrenia, as well as babies from other moms who later go
on to develop schizophrenia, already have recognizable
differences from babies who don’t carry that risk,” says Dr.
Robert Freedman. The problem, he notes, is that detecting
these differences in the first years of life is not predictive of
schizophrenia. All who develop the illness have biological
differences from the beginning; but many infants with these
differences don’t go on to become ill.
By the time of the first definitive diagnostic symptoms—
typically, a first “psychotic break,” in the late teens or early
20s—it is already too late to prevent schizophrenia from
occurring. Hence, Dr. Freedman decided to focus on
reversing or blunting the first step in the multi-step process
10 Quarterly May 2016
toward disease onset. “We thought that if we could bolster the brain’s inhibitory system even before a child is born,
then perhaps we could lessen the risk that the other biological steps toward the illness would occur. We might even
prevent the illness in some cases.”
His team demonstrated, first in rodents and then in people,
that supplying choline in high doses to expectant mothers
would suffice to activate the inhibitory system in the developing fetus. They noted that this supplementation would
bring the choline level up to levels others had measured in
the amniotic fluid of healthy mothers. The team also drew
heavily on medicine’s past success with another kind of
prenatal supplementation—that of folic acid, another vital
nutrient that expectant moms must have lest their infants
An experimental drug that targets the A-7 nicotinic receptor reduces hyperactivity in the brain’s right hippocampus (yellow),
a prime site of emotional processing and affected in schizophrenia.
suffer from neural tube defects and a variety of associated
birth defects. Folic acid fortification, ideally begun before
conception and continued throughout the perinatal period,
especially in women with poor diets, is accepted practice in
the U.S. and worldwide.
Dr. Freedman, with critical help from Camille Hoffman,
M.D., an assistant professor of maternal-fetal medicine, and
Randal Ross, M.D., a professor of child psychiatry, both at
the University of Colorado School of Medicine, took a parallel approach with choline. Led by Dr. Hoffman, who was
awarded the Foundation’s Sidney R. Baer Jr. Prize in 2015,
the team recruited 100 healthy women from the Denver
area. In a double-blind trial they tested whether giving choline supplements during pregnancy to increase the nutrient’s
level in the amniotic fluid would enhance the development
of inhibition in the fetal brain’s cerebral cortex. The supplements (twice normal dietary levels) were given by pill, twice
a day throughout the second and third trimesters, and then
to mother and newborn through the third postnatal month.
Happily, there were no adverse effects in maternal health,
delivery, birth or infant development. But did the supplements make any difference? Dr. Freedman’s team gave the
newborns a crucial test after five weeks. Each child was
exposed to two identical sounds—a succession of clicks.
The team measured the activity of the brain during this
test. A baby or adult with normal inhibition responds much
less robustly to the second sound, which is filtered out as
comparatively insignificant. A sharp response to the second
sound is what scientists call a “surrogate marker” of a deficiency in inhibition.
This marker, called the P50 response, indicated normal
inhibition in 76 percent of the infants whose mothers had
been given choline supplements. In babies whose mothers
received placebo instead of extra choline, only 43 percent
had normal inhibition. That figure would likely have been
lower if every mother in the trial, regardless of her treatment,
had not received special instructions from visiting nurses to
eat a diet rich in choline. (The aim was to compare choline
supplementation with normal, not subpar, choline intake by
the expecting mother.)
The study showed, too, that choline supplements even benefitted the infants of mothers who carried genetic risk factors
for schizophrenia, including variants of CHRNA7. But in
mothers carrying these risk factors who received placebo,
even the benefit of dietary advice (as opposed to supplementation by pill) during pregnancy did not prevent their
children from showing diminished P50 inhibition after
birth. In 2015, Dr. Freedman’s team reported follow-up
results when infants in the original trial reached 40 months
of age—the time when behavioral patterns become settled
and incipient problems are discernable.
“Children who will go on to develop schizophrenia already
have recognizable motor problems in the first year of life,”
Dr. Freedman says, “which are not in themselves diagnostic.
But by early childhood they also show clear signs of attention difficulties and social withdrawal, effects that we can
trace at least partly to deficits in inhibition.”
At 40 months, the team was excited to observe that children
of mothers who had received choline supplements had fewer
attention problems and less social withdrawal compared
with children in the placebo group. It is of course impossible to know the “final” outcome of this experiment until
the children reach their 20s. Right now, says Dr. Freedman,
“what we know is that the babies exposed to supplemental
choline as four year-olds are healthier children than if we
had not intervened.”
The team will continue to test whether the specific form of
choline used in the trial—called phosphatidylcholine—is
indeed the best supplement to give. The optimum dose also
remains under study. Have A Question?
Send questions for Robert Freedman, M.D.
to [email protected].
Select questions and answers will be in the
next issue of the Quarterly.
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